Project Summary: PAR-15-190 seeks to accelerate the pace of development of novel therapeutics for pre- venting health issues affecting the elderly. This project proposes to simultaneously treat the age-related loss of muscle function (sarcopenia) and osteoarthritis (OA). Traditionally, studies to prevent the onset of sarcope- nia and OA in human subjects are complicated by prolonged and unpredictable development/progression of the disease. This project advocates the use of a novel guinea pig model that rapidly and predictably develops naturally-occurring/spontaneous sarcopenia and OA in a manner similar to humans. The suggested treatment strategy, which targets both sarcopenia and OA, is important and logical because: 1) both conditions are pri- mary contributors to age-related loss in mobility and functional independence, 2) loss of muscle strength and OA often occur concurrently, and 3) both disorders have shared pathogenesis involving inflammation and oxi- dative stress. The long-term goal of this project is to translate previous studies focused on the basic biology of aging into viable human treatments to slow age-related impairments. The goal of this current project is to use a Nrf2 activator to slow the progression of age-related loss in muscle function and primary OA in a guinea pig model of accelerated musculoskeletal aging. The central hypothesis is that, by targeting pathways that result in the maintenance of proteostasis over time, it will be possible to slow the onset/progression of sarcopenia and primary OA. The hypothesis is supported by data indicating that: 1) maintained proteostasis is a shared characteristic of multiple slowed-aging rodent models, 2) treatment with a Nrf2 activators increases proteostatic processes in skeletal muscle, and 3) treatment with a Nrf2 activator has been shown to be safe and viable long-term treatments as demonstrated by the National Institutes of Aging (NIA) Interventions Testing Program (ITP). To accomplish these goals, the following specific aim is proposed: to examine the potential of long-term treatment with a Nrf2 activator (PB125) for preventing the onset/progression of sarcopenia and primary OA, and the age-related decline in mobility. The primary outcome of the project is improved mobility, which will be supported by mitochondrial function, histological, morphological, and proteostatic outcomes to determine slowed progression of OA and sarcopenia. This contribution is significant because sarcopenia and OA are two leading causes of age-associated disability that often occur concurrently, and treatments that effectively slow their progression are lacking. The proposed research is innovative in that it: 1) proposes an approach that treats both conditions simultaneously by targeting common mechanisms of pathogenesis, 2) uses a treatment that targets endogenous mechanisms, 3) uses a treatment with demonstrated efficacy in extending lifespan and presumably healthspan, and 4) demonstrates the efficacy of this treatment in a model that closely models the human condition, albeit in a shorter period of time. Therefore, the project accomplishes the goal estab- lished by NIA in PAR-15-190 to accelerate the pace of development of novel therapeutics for older individuals.